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. 2000 Aug 15;97(17):9701-5.
doi: 10.1073/pnas.170280697.

Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease

J Carmichael  1 , J Chatellier, A Woolfson, C Milstein, A R Fersht, D C Rubinsztein
Affiliations

Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington's disease

J Carmichael et al. Proc Natl Acad Sci U S A. .

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative condition caused by expansions of more than 35 uninterrupted CAG repeats in exon 1 of the huntingtin gene. The CAG repeats in HD and the other seven known diseases caused by CAG codon expansions are translated into long polyglutamine tracts that confer a deleterious gain of function on the mutant proteins. Intraneuronal inclusions comprising aggregates of the relevant mutant proteins are found in the brains of patients with HD and related diseases. It is crucial to determine whether the formation of inclusions is directly pathogenic, because a number of studies have suggested that aggregates may be epiphenomena or even protective. Here, we show that fragments of the bacterial chaperone GroEL and the full-length yeast heat shock protein Hsp104 reduce both aggregate formation and cell death in mammalian cell models of HD, consistent with a causal link between aggregation and pathology.

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Figures

Figure 1
Figure 1
Suppression of inclusion formation by apGroEL, MC7, Hsp104 wt, and Hsp104 K620T in COS-7 (a and b) and PC12 (c and d) cells. In all experiments, the odds ratios are derived from 2–4 independent experiments, each done in triplicate, where we have compared test constructs with pFLAG. (Error bars = 95% confidence intervals for the odds ratios.) (a) COS-7 cells cotransfected with EGFP-HDQ74 and apGroEL and control plasmids. (b) COS-7 cells cotransfected with EGFP-HDQ53 and all test and control plasmids. (c) PC12 cells cotransfected with EGFP-HD74 and apGroEL and control plasmids. (d) PC12 cells cotransfected with EGFP-HD74 and all test and control plasmids (except for apGroEL, which is shown in c). *, P < 0.05; **, P < 0.001; ***, P < 0.0001; NS = P > 0.05.
Figure 2
Figure 2
Reduction of nuclear fragmentation in COS-7 cells after coexpression of EGFP-HDQ74 (a) and EGFP-HDQ53 (b) with apGroEL, MC7, Hsp104 wt, and Hsp104 K620T. Cells were analyzed after 48 h (a) and 72 h (b). In all experiments, the odds ratios are derived from 2–4 independent experiments, each done in triplicate, where we have compared test constructs with pFLAG. (Error bars = 95% confidence intervals for the odds ratios.) *, P < 0.05; *, P < 0.001; *, P < 0.0001; NS = P > 0.05.
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